Adherence to <scp>NHLBI</scp> guidelines for the emergent management of <scp>vaso‐occlusive</scp> episodes in children with sickle cell disease: A multicenter perspective
Authors: Chris A. Rees, David C. Brousseau, Fahd A. Ahmad, Jonathan Bennett, Seema Bhatt, Amanda Bogie, Kathleen M. Brown, T. Charles Casper, Laura L. Chapman, Corrie E. Chumpitazi, Daniel M. Cohen, Carlton Dampier, Angela M. Ellison, Hartmut Grasemann, Robert W. Hickey, Lewis L. Hsu, Peter A. Lane, Nitya Bakshi, Sara Leibovich, Prabhumallikarjun Patil, Elizabeth C. Powell, Rachel Richards, Syana Sarnaik, Debra L. Weiner, Claudia R. Morris
Journal: American Journal of Hematology (2022)

To the Editor: Patients with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE), which accounts for 78% of all emergency department (ED) visits among patients with SCD.1 SCD-VOE pain is often under-, and inconsistently, treated in the ED.2 In 2014, the National Heart, Lung, and Blood Institute (NHLBI) put forth guidelines to direct the care of patients presenting with VOE.3 Key guideline recommendations include: (1) triage as high priority with rapid evaluation of patients presenting with VOE, (2) use of parenteral opioids for moderate-to-severe pain with administration ≤30 min after ED triage or ≤ 60 min after registration, (3) pain reassessment and subsequent parenteral opioid dosing every 15–30 min until pain is controlled, (4) the administration of non-steroidal anti-inflammatory drugs (NSAIDS) as an analgesic adjuvant (if no contraindications exist), and (5) in euvolemic patients with SCD-VOE who are unable to drink fluids, intravenous hydration at no more than maintenance rate to avoid over-hydration. Our objective was to assess adherence to all NHLBI recommendations and the impact of timely opioid administration on hospital admission in a study of 20 academic pediatric EDs in the United States and Canada. A cross-sectional study was performed at 20 academic, pediatric EDs across the United States and Canada (19 in the United States and one in Canada) (Supplemental Methods). International Classification of Disease Ninth and Tenth Revision code ED diagnoses of VOE were used to identify consecutive patients. To include the traditionally more severe genotypes of SCD, children with sickle cell anemia (hemoglobin-SS disease or hemoglobin Sβo-Thalassemia) aged 3–21 years who presented with VOE pain of any severity were included. Children who were diagnosed in the ED with acute chest syndrome or pregnancy were excluded. To determine adherence to the 2014 NHLBI recommendations, the date and time of: ED arrival, triage, patient rooming, initial pain assessment, intravenous (IV) catheter placement, first parenteral opioid administration (including intranasal fentanyl at some sites), pain reassessment, and second parenteral opioid administration were collected. Assigned Emergency Severity Index (ESI) triage score, type of parenteral opioid administered, IV fluid administration, and disposition from the ED were collected. ED arrival (i.e., the earliest time of ED arrival, registration, triage time, or time to room, whichever came first) was used for time to outcome measures. Descriptive statistics were calculated for adherence to each of the 2014 NHLBI recommendations for the management of acute VOE. Univariable logistic regression was used to assess factors associated with receipt of first parenteral opioid within ≤60 min and the relationship between time of opioid administration and hospital admission. Kruskal-Wallis and Wilcoxon rank-sum tests were used to test for associations between continuous variables and Chi-Square tests were used to test for associations between categorical variables. All statistics were conducted using SAS version 9.4. Over half of the 400 patients were female (n = 215, 54%) (median age 14.6 years [IQR 9.8, 17.6]). Most patients had hemoglobin-SS (92%, n = 367) and 8% (n = 33) had hemoglobin Sβo Thalassemia. MedED arrival times to evaluation and treatment were as follows: time to first pain assessment 8 min (IQR 3, 20), time to IV catheter placement 52 min (IQR 33, 81), time to first parenteral opioid administration 62 min (IQR 37, 98), and time from first to second parenteral opioid 67 min (IQR 46, 101). The proportion of children who received NHLBI recommended evaluation and treatments is in Table 1. Most patients were assigned the recommended ESI triage score of ≤2. Pain was assessed and documented in 99% (n = 395) of all charts. Most patients had pain reassessed (n = 363, 91%). Pain reassessment after the administration of the first parenteral opioid occurred at a median of 20 min (IQR 5, 46). The median number of pain reassessments per ED visit was 4 (IQR 3, 6). Site variation was observed for NHLBI guideline adherence for first parenteral opioid administration ≤60 min from ED arrival (range 0–90% adherent; range median 24–144 min), and time between first and second opioid doses (range median 29–122 min). Fewer than half of patients received parenteral opioids within the recommended ≤60 min of ED arrival (Table 1). Twenty-five percent (n = 101) received parenteral opioids ≤30 min of triage and 28% (n = 110) received parenteral opioids between 31 and 60 min after triage. Forty-three percent (n = 173) received the first parenteral opioid >60 min after triage. There was no significant difference in median time to first- or second-parenteral opioid administration based on patient age or sex (eTables 1 and 2). Children who presented during afternoon shifts were less likely to receive parenteral opioids in ≤60 min from arrival compared to overnight (eTable 3). Of 75 patients who received intranasal fentanyl as their first parenteral opioid, 65 (87%) received it ≤60 min compared with 125/314 (40%) by 60 min for those who received IV delivery of the first-parenteral opioid dose (P < 0.001). Children who received intranasal fentanyl had greater odds of receiving parenteral opioids in ≤60 min from arrival (OR 9.83, 95% CI 4.87–19.85). The median number of parenteral opioid doses administered in the ED was 2 (IQR 1, 3). There were 270 (68%) children who received ≥2 parenteral opioid doses and 6% of these received a second dose within 30 min of the first-parenteral opioid. Overall, 4.5% (n = 18) patients received both the first-parenteral opioid within 60 min from ED arrival and the second dose within 30 min of the first dose. An oral opioid was given to 98 patients (25%). IV fluids (bolus and/or maintenance fluid) were administered to 84% (n = 335) of patients.4 Intravenous ketorolac was given to 66% (n = 265) of patients (Table 1). The median ED length of stay from arrival to disposition order placed was 5 h (IQR 4, 6), and 67% (n = 268) required admission to the hospital. There was no association between time to delivery of first-parenteral opioid and admission (p = .45). Children who received their second-parenteral opioid ≤30 or ≤ 60 min from the first-parenteral opioid did not have significantly different odds of hospital admission when compared to children who received their second parenteral opioid >30 min or > 60 min, respectively. In our multicenter study of NHLBI pediatric ED SCD-VOE guideline adherence, pain was frequently and rapidly assessed. However, fewer than half of patients received parenteral opioids within the recommended 60 min, and few received both the first and second doses of parenteral opioids in NHLBI-recommended timeframes. Some institutions have adopted automated systems to universally assign high-acuity ESI scores (i.e., ≤2) to patients with SCD,5 which may help standardize this step. Given delays identified in the placement of an IV, nurse-initiated SCD-pain protocols may be a feasible strategy to improve adherence to rapid delivery of first dose of parenteral opioids. Historically, only 20% of hospitals have used SCD care protocols,6 although this practice is increasing. Quality improvement initiatives utilizing pain protocols suggest reduced time from arrival to parenteral opioid administration for VOE.7 Prior studies have not assessed the time to IV catheter placement, which could be an important bottleneck that may be targeted in future initiatives. Difficult IV access, high patient volume, and high acuity in the ED often challenge optimal timing of IV placement. Parenteral opioids remain the mainstay of treatment for SCD-VOE. Our observation of poor guideline adherence to administer timely initial parenteral opioids aligns with those in prior studies.2 Furthermore, the majority of patients failed to receive timely administration of a second dose of parenteral opioids within 30 min of the first. The creation of personalized pain management plans, use of intranasal medications including fentanyl, diamorphine, or hydromorphone, and allowing nurse-initiated administration of parenteral opioids in these plans may shorten the time to parenteral opioid administration. The American Society of Hematology recently put forth guidelines for the management of acute and chronic pain from SCD These guidelines were disseminated by the American College of Emergency Physicians. Our results serve as a baseline for future comparisons and the impact of this dissemination in the future studies is warranted. Our data do not support prior findings suggesting time between the administration of the first- and second-parenteral opioid is associated with lower odds of hospitalization. Quality improvement efforts have focused on reducing the time to administration of the first-parenteral opioid, which remains an important goal from the perspective of reducing patient suffering, though it may not reduce hospital admissions. This study has several limitations. We did not account for the role of provider implicit bias and racism which may contribute to delays in opioid administration as SCD predominately affects Black patients. We did not account for patients who may have taken oral NSAIDS or opioids prior to arrival. We also did not control for patient/parental preference for timing of opioid administration. Lastly, our findings may not be reflective of non-academic and non-pediatric facilities. Our findings highlight significant delays in the adherence to important recommendations from the NHLBI. Namely, the time to delivery of initial and subsequent parenteral opioids was suboptimal and may relate to delays in IV catheter placement. Our findings allow for targeted initiatives to increase adherence to NHLBI guidelines for the treatment of patients with SCD-VOE in the ED. Drs. Morris and Rachel Richards had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the data collection. Dr. Casper and Ms. Richards were responsible for all statistical analyses. Drs. Rees and Morris were responsible for the manuscript preparation. All authors assisted with data interpretation and revised and critically reviewed the manuscript. This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS, or the U.S. Government. This study was supported by the NIH/NHLBI under award number R34HL122557 (to CRM), and in part by NIH/NCCIH K24AT009893 (to CRM) and the Pediatric Emergency Care Applied Research Network (PECARN), supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS), in the Maternal and Child Health Bureau (MCHB), under the Emergency Medical Services for Children (EMSC) program through the following cooperative agreements: DCC-University of Utah, GLEMSCRN-Nationwide Children's Hospital, HOMERUN-Cincinnati Children's Hospital Medical Center, PEMNEWS-Columbia University Medical Center, PRIME-University of California at Davis Medical Center, CHaMP node- State University of New York at Buffalo, WPEMR- Seattle Children's Hospital, and SPARC- Rhode Island Hospital/Hasbro Children's Hospital. NB received funding from the NIH/NHLBI under award number 1K23HL140142 and 1K23HL140142-03S1, from the Doris Duke Charitable Foundation COVID19 Fund to Retain Clinical Scientists- PeRSEVERE Program at Emory University School of Medicine, and the Georgia Clinical and Translational Science Alliance under award UL1-TR002378. The funders had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation, review, approval of the manuscript, or decision to submit the manuscript for publication. No authors have potential conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject of their manuscript. A waiver of consent was granted because all data were retrospectively extracted. The data may be made available upon reasonable request. 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